Biologically active substances supplied to an organism are, in most cases, rapidly digested by the organism. In view hereof, the supply of substances must be repeated at regular intervals in order to establish a therapeutically active concentration within the organism. Such supply of biologically active substances to organisms is important int. al. in the fields of human and veterinary medicine, or in controlling different types of infestants (such as insects, fungi etc.) in agriculture and forestry.
In order to avoid the disadvantages of repeated administration, it is endeavoured to find matrices which, together with the substance, provide a depot effect, by which is meant that the substance in one way or another is adsorbed, coupled to or enclosed in a matrix from which it is then released, via different mechanisms, during a prolonged period of time. The great advantage of this type of administration is that the substance is supplied to the organism at a uniform rate; the peaks and valleys in concentration encountered with normal administration are avoided. By biologically active preparations are meant such preparations or substances as are capable of affecting organisms. Examples of such preparations are therapeutically active preparations, insecticides or herbicides, enzymes, antibodies, antigens, allergens, hormones, live or killed and whole or decomposed microorganisms or virus. As practical examples of the fields of use of the present invention, mention may be made of
1. Insulin: Patients suffering from diabetes must inject insulin at regular intervals or during meals in order to maintain the blood sugar content at an acceptable level. Great advantages would be obtainable if a depot preparation of insulin could be administered in a simple manner, implying that the injection frequency could be reduced considerably;
2. Vaccination: For the vaccination of humans, adjuvants cannot be used. However, it has been shown in literature that the immunogenic response will be far better if the body is subjected to long-time exposure of the antigen. For vaccination purposes, it is important that the depot matrix is not itself immunogenic, and that it can be excreted from the body. For example, vaccination tests conducted on human beings against bee allergens have shown that these allergens, dissolved in water and injected subcutaneously, are excreted within 4 hours.
The production of depot matrices for different types of preparations is well-documented in literature, and some preparations are also commercially available.
The invention described in the present application uses polymers as depot matrix. Different types of polymers are described in literature. (Chem. Eng. Commun. (1980) 6, 1-48 or Int. J. Pharm. (1980) 7, 1-18). Among the desirable properties of such a polymer preparation are the following:
1. The polymer should in itself be chemically inert in biological systems.
2. The polymer should be biologically well-characterised.
3. The polymer should be non-toxic and non-immunogenic.
4. The polymer should be excretable from the body via normal routes.
5. The polymer preparation should be readily administrable.
6. The polymer preparation should be capable of releasing a biologically active substance, and the release rate of the active substance should be readily controllable.
7. The polymer preparation should be able to enclose and release substances of different molecular weights.
Existing polymer systems described in the above-mentioned summary reviews are all of the type covalently cross-linked polymers in which the covalent cross-linkage in some cases is unstable in biological systems, and in which the biologically active substance is covalently bonded to the polymer. This instability causes degradation of the polymer preparation, whereby the preparations are released.
A different type of release is obtained if crystalline substances (such as crystallised proteins) are enclosed in the covalently cross-linked polymer preparation. By utilising a varying degree of porosity in the polymer preparation, varying release times are obtained.
In general it may be said that it is endeavoured, in developing polymer preparations for administration of biologically active substances, to use polymers which are as "pure" as possible. One such "pure" polymer class is represented by the carbohydrates. Presentday methods of preparing carbohydrate matrices comprise a covalent coupling of the polymer chains included (GB Pat. No. 924054) or heat treatment (SE Pat. No. 4024/69) in order to obtain stable matrices.